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Methods for treating EGFR mutant cancers

a technology for egfr mutant cancer and treatment methods, applied in the direction of drug compositions, heterocyclic compound active ingredients, anti-cancer agents, etc., can solve the problems of ineffective treatment of egfr inhibitors, limited clinical efficacy, and inability to definitively translate into prolonged overall survival

Active Publication Date: 2018-05-03
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]The present invention relates to the use of (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1Hbenzo[d]imidazol-2-yl)-2-methylisonicotinamide (Compound A), or a pharmaceutically acceptable salt thereof. A particularly useful salt of C

Problems solved by technology

Their clinical efficacy has however proven to be limited, possibly due to severe adverse effects caused by concomitant wild-type (WT) EGFR inhibition.
Treatment with EGFR inhibitors has however not been shown to definitively translate into prolonged overall survival.
Currently there is also no effective therapy available to target Ex20ins mutants, thus an unmet medical need exists.

Method used

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  • Methods for treating EGFR mutant cancers
  • Methods for treating EGFR mutant cancers
  • Methods for treating EGFR mutant cancers

Examples

Experimental program
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Effect test

example 1

7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGFRi) Biochemical Assays

[0108]IC50 Determinations.

[0109]All EGFR biochemical assays were carried out as described in WO2013 / 184757.

[0110]Biological Results

[0111]IC50 determinations for Compound A obtained from a EGFR biochemical assay as described above from EGFR (L858R / T790M) without and with 90-minute pre-incubation were 0.008 μM and <0.001 μM, respectively.

[0112]Compound A shows an inhibition IC50 determinations obtained from EGFR target modulation in engineered NIH / 3T3 cell lines for L858R / T790M and L858R, 0.011 μM and 0.015 μM, respectively. For WT the value was 0.259 μM.

[0113]The IC50 determinations obtained from EGFR target modulation in H1975 (EGFR L858 / T790M), H3255 (EGFR L858R), and HEKn (EGFR WT) cell lines were 0.013 μM, 0.030 μM and 1.180 μM respectively.

example 2

Salt and Mesylate Form B (Mesylate Trihydrate Form) of Compound A

[0114](R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide as obtained in Example 5 of WO2013 / 184757 (1.0 g) was dissolved in acetone (30 mL) by heating to 55° C. to form a solution. Methanesulfonic acid (325 μL) was added to acetone (50 mL), and the methanesulfonic acid / acetone (22.2 mL) was added to the solution at 0.05 ml / min. Following precipitation, the resulting suspension was cooled to room temperature at 0.5° C. / min, and crystals were collected by filtration, and dried for 4 hours at 40° C. under vacuum. The collected crystals (300 mg) were suspended in acetone / H2O (6 mL; v / v=95 / 5) by heating to 50° C. The suspension was kept slurrying for 16 hours, and cooled to room temperature at 0.5° C. / min. The crystal was collected by filtration and dried for 4 hours at 40° C. under vacuum.

[0115]The structure of (R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-e...

example 3

Compound A (EGF816) on EGFR Exon 20 Insertion Models in in Vitro Cell Assays

[0117]3.1 Cell Lines

[0118]NIH-3T3 Ex20_D770_N771insNPG cells (obtained from DFCI) were maintained in 10% FBS / DMEM P / S media supplemented with 2 μg / mL puromycin. Engineered BaF3 cells were maintained in 10% FBS / RMPI P / S media supplemented with 2 μg / mL puromycin. All cells were maintained in a humidified incubator at 37° C. with 5% CO2.

[0119]Full-length, wild-type EGFR cDNA was sub-cloned into the cloning vector pCR4 (LifeTech) and used as a template to create Ex20ins mutants D770_N771insSVD and V769_D770insASV with a site-directed mutagenesis kit (Agilent). Sequence-verified clones were double-digested with endonucleases XhoI and HpaI and ligated to similarly digested pMSCVpuroLuc expression vector (in-house). HEK293T cells were co-transfected with mutant EGFR pMSCVpuroLuc vector and pEcoPak viral packaging vector. Supernatants containing viral vectors were subsequently used to infect IL-3 dependent BaF3 cell...

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Abstract

Methods for the treatment of EGFR mutated cancer. For example, treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations (e.g., L858R and ex19del) the acquired or resistant “gatekeeper” T790M mutation, or any combination of these mutations.

Description

BACKGROUND OF THE INVENTION[0001]Lung cancer is the most common cancer worldwide, with NSCLC accounting for approximately 85% of lung cancer cases. In Western countries, 10-15% non-small cell lung cancer (NSCLC) patients express epidermal growth factor receptor (EGFR) mutations in their tumors and Asian countries have reported rates as high as 30-40%. The predominant oncogenic EGFR mutations (L858R and ex19del) account for about 90% of EGFR NSCLC.[0002]Besides the classic EGFR mutations (L858R and Ex19Del), EGFR Exon 20 insertion mutations (Ex20ins) were described to account for 4-10% of all EGFR mutations in patients, the third largest EGFR mutant patient population behind the classic (L858R and ex19del) EGFR mutations. EGFR Exon 20 insertion mutations include EGFR 20 duplication mutations.[0003]EGFR-mutant patients are given an EFGR inhibitor as first line therapy. However, most patients develop acquired resistance, generally within 10 to 14 months. In up to 50% of NSCLC patients ...

Claims

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Application Information

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IPC IPC(8): A61K31/55A61P35/00
CPCA61K31/55A61P35/00
Inventor LE, NGOCDIEPLELAIS, GERALDJIA, YONG
Owner NOVARTIS AG
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